Monday, June 07, 2021

Random musings on uncoupling (4) coconut

Feeding mice on a high sucrose, low linoleic acid diet activates FGF21 production by the liver which stimulates heat generation in brown adipose tissue, leading to a lean phenotype, marked insulin sensitivity and poor glucose tolerance secondary to down regulated glucokinase in the liver. This latter is not surprising as fructokinase has a much higher rate constant for fructose phosphorylation than glucokinase does. Use it or lose it applies, even if only temporarily, so glucokinase down regulates. A bit like eating a low carb diet also down regulates glucokinase.


Edit, this one too


End edit

My basic feeling was that fructose generated a caloric overload in the liver. Rather than dealing with this issue using hepatocyte mitochondrial uncoupling the task of dealing with the excess was delegated to brown adipose tissue and FGF21 was the messenger. "Higher  level" signalling. BAT uncouples on behalf of the liver. 

Of course that immediately suggests that other caloric overloads, especially if uncontrolled, might do the same thing. George Henderson tweeted this paper, which I've known about for years but have never gone in to in great detail:

Long term highly saturated fat diet does not induce NASH in Wistar rats

I hadn't realised how much uncoupling these rats were doing. They all weighed pretty much the same but caloric intake was way higher in the butter fed rats and even higher still in the coconut fed rats. That's interesting compared to coconut oil used in the Surwit type diets but these current diets are low in PUFA and sucrose free. Here are the caloric intakes:

















The coconut based diet was particularly interesting as the rats were consuming twice the calories of the chow fed rats and weighed exactly the same. You could argue that coconut just tastes better than chow and the rats over ate then uncoupled. Or, more interestingly, you could suggest that medium chain fatty acids enter liver mitochondria in an unregulated manner and generate large amounts of input to the electron transport chain. If hepatocytes are experiencing a caloric overload what else should they do other than generate FGF21 and sub contract a calorie disposal solution to the BAT?

This arrangement would benefit, as with fructose, from the hepatocytes being the primary cells targeted to receive the unregulated caloric supply and is a good reason for keeping MCTs out of chylomicrons and passing them directly to the liver via the portal vein. Which is what happens.

So we can look at this study (just ignore everything about stress response and how a few ketones will do horrendous things to you):

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21

Here is what gavaging a chow fed rat with MCT oil does to FGF21 an hour later


















LCT stands for corn oil. The acute effect of a low dose is almost nothing. Corn oil enters the systemic circulation in chylomicrons via the thoracic duct. It will be obesogenic as per ROS/Protons and only very mildly stimulating of FGF21 generation. Long term at high dose rates it will, as we've noted, uncouple enough to offset the metabolic syndrome induced as per ROS/Protons and result in a slim rodent which needs to over eat mildly to compensate for the side effect of uncoupling.

After coconut oil the uncoupling effect via FGF21 is marked so the compensatory eating has also got to be marked because the primary source of calories floods liver mitochondria with medium chain fatty acids.

So......... Localised hepatic caloric overload is a stimulus for FGF21 production leading to BAT thermal caloric disposal. As far as the rest of the body is concerned there is just the BAT caloric loss induced deficit to be perceived. There is a hypercaloric state in hepatocytes and a hypocaloric state in other systems, hypothalmus included. Food intake rises to maintain a normal energy supply to avoid weight loss.

Note the arrow of causality. The rats/mice are not over eating and burning off the excess. They are eating extra using an appropriate appetite to cope with BAT calorie expenditure/loss. They might not want to be hot but they have no choice. They eat to make up for it.

Peter

BTW there is this:

with alcohol being another hepatocyte caloric overload source which also generates FGF21 to "dispose" of the excess hepatic calories via BAT.

Using AMPK.

Which is where things get complicated.

19 comments:

Passthecream said...

This is getting interesting, lots to comprehend here.


These people are making a BATlas of the human body:

https://www.pnas.org/content/114/32/8649

Peter said...

Cool. They'll be on to FGF12 next! The guy with the phaeo is (was?) fascinating.

Peter

Puddleg said...

An interesting sideline on this is that increasing the workload of hepatocytes by a much higher fat energy turnover from coconut oil is doing nothing to increase their vulnerability to inflammation. It was one of the basic assumptions of fatphobic dietetics that the liver could be "overworked".
The GI concept is controversial but it seems clear that the more rapidly ingested carbohydrates are more metabolically stressful in excess.
It also seems clear that the most rapidly ingested fatty acids are the least metabolically stressful in excess.

Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans

https://diabetes.diabetesjournals.org/content/70/1/91

This seems a pretty clear "metabolic advantage" in favour of LCHF within any food system that supplies energy in the form of refined ingredients.

JR said...

Hi
do they ever measure and compare body temperatures? the difference should show? An italian study thin alcoholics vs. moderate found the same; alcoholics consumed >10% of calories than their control group (40% was alcohol, dry wine probably). As per passthecream's comment, BAT seems to be located near armpits, so temperature comparison would show something? anybody felt warm while boozing?
JR

Peter said...

Hi JR, in some studies they do but it's affected by the ambient temperature. It's much easier to maintain a normal temperature if heat loss is easy. It would probably show best in a thermo-neutral environment.

I have to say on the odd occasion I've overdosed on ethanol, waking up at 2am feeling very hot and sweaty has been a feature some times.

Peter

Eric said...

Sorry for posting completely off topic.
https://www.nytimes.com/2021/06/13/opinion/covid-vaccine-research-mixing.html?smid=url-share

Why would vector vaccines predominantly trigger T-cell response? My understanding is that the vector virus is just a ferry, the same as the lipid shell of mRNA vaccines. So with both kinds of vaccine we end up with mRNA in the cell and the cell producing spike protein and maybe presenting it on its surface which should trigger antibody response.

Thanks

Peter said...

I don't know Eric but there may be all sorts of differences in terms of where the mRNA is actually delivered. If the vector has a preference for T cells, ie the immune system itself, it might well do something different to a lipid nano particle which predominantly targets endothelial cells as the commonest off-target damage.

My personal feeling is that both will do collateral damage, it will be near universal and mostly it will not be enough to kill you or get reported. But "very rare" lethality will be one end of a spectrum of universal damage.

There are still snippets leaking out from Israel which suggest that the all cause mortality increase after vaccination may not be trivial and the vaccines will need to be saving a lot of lives in the under 60s to justify themselves.

In the mean time the psychopaths who run the UK are floating coercion of young children to be vaccinated to allow them to attend school in September.

Peter

Eric said...

Peter, I found some paper by Sarah Gilbert from 2012 in which she touts her delivery system as enhancing T-cell immunity. Haven't had time to read and understand yet:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246649/

What is the primary target cell of the lipid packaged mRNA vaccine and why would the secondary target be endothelial cells rather than hepatic?

I read your piece about decreased immunity in the first week after mRNA vaccination and have linked to it in several places. Do you have newer numbers and are planning an update?

My take home is that I will try to get vaccinated now that numbers are very low (in Germany, that is) and I am still working from home. Not because I am afraid of the Kent variety that is prevalent here but because I don't trust what will be here in winter.

Oh, and I appreciate that you use the correct word psychopath:) Less smart sceptics in the US, the UK and Germany are parroting each other about the sociopaths in power.

You might find it interesting that the German vaccination board (STIKO) last week declined recommending vaccination for 12 - 17 year olds unless they have specific comorbidities. As a result, they cannot get a vaccination slot at one of the vaccination centers nor can there be vaccination drives in school or participation made contingent on vaccination. If parents really feel there is a need, they have to go through the pediatrician or GP.

https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/23/Art_01.html
(this page and the PDF at the bottom were not translated but Deepl does a decent job)

Peter said...

Eric, as far as I know the intended target is the muscle cells of the deltoid. Where the vector leaks to after that is anyone's guess and one of the concerns voiced to the EMA (and remain unanswered because no one has checked) is where else the mRNA ends up being delivered.

For interest, the attempt to develop and market an RSV vaccine for children was pulled due to ADE, except it wasn't antibodies doing the damage, it was cell mediated enhanced viral damage. Immune mediated enhancement is a better term.

Yes, anyone planning on getting the vaccine would do well to get it now.

Mind you, the Delta variant appears to present as a headache and runny nose. No cough. So is claimed on twitter anyway. That's just what viruses do. They become more contagious (not much evidence for this in our variants, Kent, India, Delta all the modelling is bollocks) while simultaneously becoming less virulent. It's just evolution. Which viruses do.

SARS-1 was decreasing in virulence from very early on it it's brief foray among humans.

Peter

Eric said...

Peter, so your comment about the secondary target being endothelial cells were not hinting at a special property of these cells other than that they are in the path of the vaccine if it leaks?

Hadn't heard about the headache and runny nose part. Hardly what would cause untold mayhem in India, so what happened there? We are told that Delta as it circulating in England is both more contagious and more virulent.

Eric said...

Admittedly, these are US data for mid Dec to mid Jan, but they say fewer vaccinated people died of MI and other CV issues than would be expected for their age groups:
https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm

Peter said...

Yes, we are told all sorts of things which defy established virology. Someone should have told Pasteur that viruses become more virulent with time as he successfully attenuated the rabies virus using repeated passage through rabbits to make it safe for use in treating humans bitten by rabid dogs. The current pandemic has seen the eradication of science. Mostly what you get is advertising for Pfizer. CDC is not coming out of this well.

Personally I'm waiting 'til we get the Florida or Texas variants. Then we can just ignore them, as they currently do all variants in Texas and Florida!

Peter

Eric said...

https://www.theguardian.com/world/2021/jun/14/delta-variant-of-covid-spreading-rapidly-and-detected-in-74-countries

"The World Health Organization designated Delta as a variant of interest in April and a variant of concern on 11 May. It appears to cause more severe symptoms, according to evidence seen from India and elsewhere, including stomach pain, nausea, vomiting, loss of appetite, hearing loss and joint pain.

The evidence from Guangzhou in China, in particular, has been concerning. There, health officials have reported 12% of patients becoming severely or critically ill within three to four days of the onset of symptoms – up to four times higher than in previous outbreaks – and sick individuals infecting more people."


To me that sounds more like at least a full blown nasty flu than a runny nose & headache thing. In the end, the important question is how man people need to be hospitalized or even die. China may be a bad example as people "missed out" on about a year of virus and their vaccines maybe were not that great. In India, there was massive excess mortality, by all reports. Was that because they had not been exposed before or because that had a pre-delta outbreak on top?

I suppose there just aren't any high risk folks left in the UK to catch Delta, and it will be difficult to compare those (previously mildly infected or maybe even vaccinated?) who do catch it today to previous similar demographics?

Peter said...

Eric, India has a COVID-19 death rate of 271/million pop. Deaths peaked at around 4,500/d in late May. 27,000 people die every day in India because no one lives for ever. Many of the 4,500 who died "of" COVID-19 will be in categories of age/illness that they were due to die soon of their co morbidities.

You must really be much more careful about mistaking the Guardian for a source of reliable information. As bad as the BBC currently. Careful about "by all reports".

Peter

Eric said...

Not just the guardian. There have been many reports about funeral pyres happening in parking lots and firewood becoming scarce.

https://www.economist.com/asia/2021/06/12/more-evidence-emerges-of-indias-true-death-toll-from-covid-19



Same with mass graves in Manaus when P1 hit around the turn of the year after they had already had a devastating first wave and everybody was supposed to be immune.



I too am waiting for more contagious but less virulent strains to appear but at least in India and Brasil, those strains were not less virulent. Not sure what we can assume about immunity in India prior to the Delta wave, but Brazil should have had plenty. That's why the UK is currently a canary in a coalmine and we can learn if they are less virulent after most of the population have had some exposure to wild type or Alpha or vaccines.



The picture I have in my mind is that herd immunity has been claimed so many times (London, Stockholm, Manaus, ...) and each time we were surprised, so maybe each new variant reinfects many who've had a mild case. But in the end, outcomes matter, so not positive test but how many are severely ill or even die.





This NYT article does not even look at the Delta wave, but it is interesting in that it estmates seropositivity at the turn of the year at roughly 20% of the whole population.

https://www.nytimes.com/interactive/2021/05/25/world/asia/india-covid-death-estimates.html?smid=url-share



---

Lest I need another OT post, here's an update on the Uni Frankfurt group that I posted about before. They have a preprint out, and the interview is also quite interesting (again, most of you will have to Deepl it). The professor seems very aware of the problems of the various approaches to making a vaccine. In particular, he says that AZ neglected to repair splicing sites in the spike genome so that soluble spike proteins can be made. If a couple of holes in swiss cheese align, this can lead to the outcomes we have seen. He also makes a surprisingly bold statement that Johnson & Johnson as an experience vaccine manufacturer has seen and fixed those splicing sites, as evidenced by their 10x lower thrombosis rate.

https://www.researchsquare.com/article/rs-558954/v1

https://www.heise.de/hintergrund/Forscher-entraetseln-spaete-Thrombose-nach-Corona-Impfung-6068797.html

Gyan said...

Mortality figures are being adjusted in India. It was reported in late April that correct numbers were being understated by 2-5 times.

Peter said...

Gyan, of course. And the UK figures are being adjusted downwards. And the total numbers of "cases" are only for a positive PCR at 40 cycles for most of the pandemic. All of the figures are junk and the press only selectively publishes to reinforce fear. India was useful for this. Now cases are dropping there so it's back to the scariants.

All cause mortality is the only reasonable metric and even that will be delayed somewhat. And that too is skewed due to the deaths directly caused by lockdowns (in countries which can afford the "luxury" of lockdowns) being indistinguishable from deaths from or with COVID. More people may well eventually die from long term effects of lockdowns than COVID. Being pauperised is bad for your health.

Peter

karl said...

@Peter
Well said. Fear sells - but not just news.

We are in a strange time - one should note that debates and discussions on ways to reduce mortality produced by Bret Weinstein with front-line medical researchers have been taken down by people with a YT portal - apparently because it might effect the profits of a pharmaceutical company. ( there are other places where you can find these clips - and while I mostly avoid video content - these are worth the watch if only to understand what is happening to our culture. )

Even US senate testimony has been taken down by YT because they didn't like it.

( It can be seen on C-span
https://www.c-span.org/video/?507035-1/medical-response-covid-19 )

Notable that one day later, Fauci Inc. announced $3B to fund patentable versions of the same basic drugs..

The scale of the money involved means one should follow Scott Adam's advise and ignore all news-narratives - apparently the amplification of the crises helps the money flow - This is a rather nasty virus - but making it sound ever worse is now the mission of some people.

I thought that finding 'high-fat' papers that had no fat was jaw dropping - but now I see that something dire has happened to our institutions - we have lost something precious.

Hiding and distorting knowledge is a crime against humanity.

What is now obvious, is that the official information sources are simply propaganda as well. The good news is that the younger generation 'gets it' - they don't watch and don't even notice it when they step over the dying corpse of corporate news outlets. They are amazingly cynical. Sadly- perhaps not cynical enough?

Peter said...

You give me a little hope karl. My impression was that many children buy in to the whole mainstream narrative. Teenagers and those in their 20s perhaps less so. Party time!

The absolute state control of the narrative in the UK is extraordinarily disturbing and effective.

I still wonder if this is how our current civilisation begins its demise.

Peter